Mitochondria‐Targeted Nanozyme Reprograms Dendritic‐Cell Immunometabolism via Microenvironment‐Responsive CO Release to Treat Periodontitis

Inflammatory diseases are characterized by overactivated immune responses and a disrupted metabolic equilibrium, particularly in dendritic cells (DCs), where mitochondrial reactive oxygen species (mtROS) burst and metabolic reprogramming drives pathological maturation. While modulating immunometabolism is a promising therapeutic avenue, achieving subcellular-targeted delivery of bioactive molecules remains a formidable challenge. Here, we report a mitochondria-targeted nanozyme designed to concurrently scavenge mtROS and reprogram DC metabolism for effective anti-inflammatory therapy in periodontitis. This system is constructed based on Prussian blue nanoparticles (PB NPs) loaded with manganese carbonyl, a high oxidative stress-responsive carbon monoxide (CO) donor, and further modified with triphenylphosphine for mitochondrial targeting. This nanozyme efficiently accumulates in the mitochondria of activated DCs, where it efficiently scavenges mtROS and concurrently delivers controlled CO release, synergistically modulating DC function. Metabolomics analysis reveals that CO suppresses DC maturation by reprogramming cellular metabolism, including inhibiting the tricarboxylic acid cycle, modulating glycolysis, and disrupting fatty acid synthesis. Consequently, the synergistic action of PB NPs and CO effectively reverses the pro-inflammatory phenotype of DCs, reshapes the immune microenvironment, and ultimately alleviates periodontal inflammation in vivo. This work presents a promising strategy for curing inflammatory diseases by targeting metabolic reprogramming at the subcellular level.